Sympathetic Neurofunction Testing in Gestational Hypertension and Relationship with Developing Preeclampsia and Eclampsia: Real-world Evidences from Clinical Pharmacology Clinics.

BACKGROUND: Gestational hypertension carries a high-risk for adverse maternal and fetal outcomes, and it can also develop into preeclampsia. A relative decrease in parasympathetic and increase in sympathetic activity has been seen in normal pregnancy which returns to baseline after delivery. The present study aimed to detect any abnormality in sympathetic neurofunction in gestational hypertension and to identify its possible association with the development of preeclampsia/eclampsia. METHODS: A prospective, observational study was carried out among gestational hypertensive patients between 24 and 26 weeks of gestation, who were sent to clinical pharmacology clinics for autonomic neurofunction testing, along with their 24-hour urinary protein testing reports. Preisometric handgrip (IHG) and post-IHG differences in diastolic blood pressure (DBP) were noted. The association between Δ DBP and the development of eclampsia/preeclampsia was probed. RESULTS: A total of 52 pregnancy-induced hypertension (PIH) participants, both multigravida (n = 15) and primigravida (n = 37) were included in one arm (PIH arm), and 52 matched (age and gravida) pregnant women, those do not have PIH included in another arm for comparative analysis. On comparing the PIH arm and normal arm, prehand grip DBP (p ≤ 0.0001), posthand grip DBP, and Δ DBP were significantly higher in the PIH arm. Correlation between Δ DBP and 24 hours' proteinuria was observed in the PIH arm, with a significant positive correlation. CONCLUSION: A high-rise in DBP post-IHG exercise is associated with gestational hypertensive mothers and this rise is strongly correlated with the development of preeclampsia and eclampsia, which suggests that addressing sympathetic hyperactivity could be a potential area to target therapeutics while managing gestational hypertension.

Safety of hydroxychloroquine in healthcare workers for COVID-19 prophylaxis.

BACKGROUND & OBJECTIVES: Hydroxychloroquine (HCQ), reported to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in in vitro studies, has been recommended for prophylaxis of COVID-19 in healthcare workers (HCWs). The objective of this study was to assess short-term adverse events (AEs) of HCQ in HCWs. METHODS: This cross-sectional study among consenting HCWs taking prophylaxis and working in hospitals with COVID-19 patients used online forms to collect details of HCWs, comorbidities, prophylactic drugs used and AEs after the first dose of HCQ. Verification of dose and AEs was done by personal contact. Multivariate logistic regression analysis was done to determine the effect of age, gender and dose of HCQ on AE. RESULTS: Of the 1303 HCWs included, 98.4 per cent (n=1282) took HCQ and 66 per cent (n=861) took 800 mg as first day's dose. Among the 19.9 per cent (n=259) reporting AEs, 1.5 per cent (n=20) took treatment for AE, none were hospitalized and three discontinued HCQ. Gastrointestinal AEs were the most common (172, 13.2%), with less in older [odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.89], with more in females (OR 2.46, 95% CI 1.78-3.38) and in those taking a total dose of 800 mg on day one compared to a lower dose. Hypoglycaemia (1.1%, n=14), cardiovascular events (0.7%, n=9) and other AEs were minimal. INTERPRETATION & CONCLUSIONS: HCQ prophylaxis first dose was well tolerated among HCWs as evidenced by a low discontinuation. For adverse effects, a small number required treatment, and none required hospitalization. The study had limitations of convenience sampling and lack of laboratory and electrocardiography confirmation of AEs.

Ivermectin and Hydroxychloroquine for Chemo-Prophylaxis of COVID-19: A Questionnaire Survey of Perception and Prescribing Practice of Physicians vis-a-vis Outcomes.

BACKGROUND: Chemoprophylaxis (CP) along with masking and physical distancing seem an undeniable alternative. Considering the significant but uncertain role of CP for the current COVID-19 pandemic situation, we aimed to determine the various aspects of CP prescribing practices among physicians across India. METHODS: An online survey was conducted among prescribing physicians across India where physicians were assessed for their prescribing practices on COVID-19 CP. Responses to the questionnaire were obtained via telephone, email and WhatsApp messages. Responses were duly analyzed thereafter. RESULT: Ivermectin was the preffered choice in 44% individuals followed by hydroxychloroquine in 34% individuals. Odds of COVID contact among those using HCQ and / or IVR prophylaxis was less than 1 of which IVR was found more protective. The present study also made a survey among 309 community dwellers, where odds of contacted COVID among those with any prophylaxis was 0.46 times than those without any prophylaxis. CONCLUSION: The HCPs found IVR to have a greater risk reduction than with HCQ; while the combination showed the greatest reduction and lack of CP use was associated with a high risk of SARS-CoV-2 infection.

Effect of Angiotensin Converting Enzyme Inhibitors/Angiotensin Receptor Blockers on COVID-19 outcome: A Record Based Observational Study in West Bengal.

BACKGROUND: Since its first identification in December 2019, in WUHAN (CHINA), SARS-COV-2, causative agent of Corona virus pandemic, has affected millions of people worldwide, causing thousands of death. There is much speculation about the interplay between ACEI/ARB and Corona virus infection, as for internalization into host cell SARS-COV-2 binds through S spike protein to ACE-2, aided TMPRSS2. METHODS: A record based observational study has been conducted (data obtained from the clinics of fourteen physicians) in two worst affected districts of West Bengal, to find out the association of ACEI/ARB on patients, suffering from Corona virus infection. The study-protocol has already been approved by Clinical Research Ethics Committee of Calcutta School of Tropical Medicine. (IEC Ref. No: CREC-STM/2020-AS-37) Results: Increasing age, male sex and presence of co-morbidities (viz. Diabetes, COPD) are significantly associated with the occurrence of moderate and severe disease. Drugs (viz. ACEI/ARB), though are associated with less severe disease, have not achieved statistical significance, in the present study. CONCLUSION: Drugs, like ACEI/ARB, should be continued in patients suffering from COVID-19 infection, (if they are already on these drugs).

Risk Benefit Analysis in Reference to use of LMWH in COVID-19.

Venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) are frequent cardiovascular and/or respiratory complications among hospitalized patients of COVID-19 infection. A relatively high mortality of severe coronavirus disease 2019 (COVID-19) is worrying, and the application of heparin in COVID-19 has been assessed and recommended with some expert consensus because of the risk of DIC and venous thromboembolism. However, "Risk Benefit Analysis" on the aspect of safety in using low molecular weight heparin (LMWH) in COVID-19 patients for thrombosis prophylaxis has been explained below with a few case studies and detailed information from various clinical evidence. COVID-19 infection has been associated with inflammation and a prothrombotic state, with increase in fibrin, fibrin degradation products, fibrinogen, and D-dimers. Heparin treatment including unfractionated and low molecular weight heparin appears to be associated with better prognosis in severe COVID-19 patients with coagulopathy. Major studies since the onset of this pandemic, found better prognosis in severe COVID-19 patients meeting SIC criteria or with markedly elevated D-dimer, by approaching thrombosis prophylaxis with LMWH.

Comparison of the safety and efficacy of fixed-dose combination of arterolane maleate and piperaquine phosphate with chloroquine in acute, uncomplicated Plasmodium vivax malaria: a phase III, multicentric, open-label study.

BACKGROUND: Chloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria. METHODS: Patients aged 13-65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days. RESULTS: In per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100% (140/140) in the FDC of arterolane maleate and PQP group, and 99.3% (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9% (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95% CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4% in the FDC of arterolane maleate and PQP group and 85.4% in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1%), headache (1.3 vs 3.2%) and prolonged QT (1.9 vs 3.2%). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h. CONCLUSIONS: The study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile. Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129.

A Case of Self-treatment Induced Recurrent Fixed Drug Eruptions Associated with the Use of Different Fixed Dose Combinations of Fluoroquinolone-Nitroimidazole.

A young male patient used fixed dose combinations of different fluoroquinolones and nitroimidazoles several times in the last few years for self-treating repeated episodes of diarrhea and loose motion. Each time, he experienced fixed drug eruptions that increased in number and severity on subsequent occasions. Suspecting association between the drug and the rashes, the patient each time discontinued the treatment prematurely, and preferred to switch to a similar formulation next time, but with different molecules of fluoroquinolone (ciprofloxacin or ofloxacin) and nitroimidazole (tinidazole or ornidazole). He could not however avoid the rash. This time the patient presented with multiple, round-to-oval, well-defined, hyperpigmented cutaneous patches of different dimensions, all over the body. He appeared to have run out of options and therefore consulted us seeking advice on how he should treat himself next time he suffered from diarrhea. Causality assessment by Naranjo's algorithm revealed a definite relationship between the cutaneous adverse reaction and the offending drug. He was counselled regarding medication in general and advised, in particular, to avoid the tendency to self-treat any future episode of diarrhea.

Efficacy of Early Intervention for Infants With Cerebral Palsy in an LMIC: An RCT.

OBJECTIVE: To test efficacy of a parent-delivered multidomain early intervention (Learning through Everyday Activities with Parents [LEAP-CP]) for infants with cerebral palsy (CP) compared with equal-dose of health advice (HA), on (1) infant development; and (2) caregiver mental health. It was hypothesized that infants receiving LEAP-CP would have better motor function, and caregivers better mental health. METHODS: This was a multisite single-blind randomized control trial of infants aged 12 to 40 weeks corrected age (CA) at risk for CP (General Movements or Hammersmith Infant Neurologic Examination). Both LEAP-CP and HA groups received 15 fortnightly home-visits by a peer trainer. LEAP-CP is a multidomain active goal-directed intervention. HA is based on Key Family Practices, World Health Organization. Primary outcomes: (1) infants at 18 months CA: Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT mobility); and (2) caregiver: Depression Anxiety and Stress Scale. RESULTS: Of eligible infants, 153 of 165 (92.7%) were recruited (86 males, mean age 7.1±2.7 months CA, Gross Motor Function Classification System at 18 m CA: I = 12, II = 25, III = 9, IV = 18, V = 32). Final data were available for 118 (77.1%). Primary (PEDI-CAT mobility mean difference = 0.8 (95% CI -1.9 to 3.6) P = .54) and secondary outcomes were similar between-groups. Modified-Intention-To-Treat analysis on n = 96 infants with confirmed CP showed Gross Motor Function Classification System I and IIs allocated to LEAP-CP had significantly better scores on PEDI-CAT mobility domain (mean difference 4.0 (95% CI = 1.4 to 6.5), P = .003) compared with HA. CONCLUSIONS: Although there was no overall effect of LEAP-CP compared with dose-matched HA, LEAP-CP lead to superior improvements in motor skills in ambulant children with CP, consistent with what is known about targeted goal-directed training.

Unravelling the apoptotic mechanisms in T-lymphocytes in an animal model for pollen induced airway allergy and studying the impact of specific immunotherapy.

Asthma is a chronic inflammatory disorder of the airways, increasing in prevalence worldwide. Reduced T cell apoptosis may interfere with the down-regulation of an immune response resulting in T cell accumulation contributing to the chronic inflammation of asthma. Most studies focused so far on apoptosis of eosinophils but the detailed role of T lymphocytes apoptosis in allergic diseases is unclear yet. The present experimental study was designed to discern the modulation of various apoptotic proteins of splenic T lymphocytes in a previously established rat model of Alstonia scholaris pollen induced airway allergy. Flowcytometry, immunoblotting, and immunofluorescence imaging techniques were employed for the present investigation. Annexin-V studies registered early apoptotic rate of lymphocytes with allergen sensitization and challenge which was corrected following mucosal immunotherapy. The study demonstrates that allergen sensitization and challenge reduced apoptosis of splenic T-lymphocytes via Fas mediated extrinsic pathway, Bax/Bcl2 regulated intrinsic pathway and also perforin/granzyme mediated pathway which were normalized following allergen specific intranasal immunotherapy. Inadequate T cell apoptosis in asthma appears to interfere with normal T cell elimination, resulting in T cell accumulation, which contributes to chronic inflammation and may be the major underlying cause for tissue damage which can be modulated by intranasal immunotherapy. Thus the apoptosis inducing effect of allergen immunotherapy necessitates more studies to elaborate on its effects on various effector cells of airway inflammation.

A Case of Inappropriate Self-Medication Compounded with Prescribing vis-à-vis Dispensing Errors and the Hazardous Consequence.

INTRODUCTION: Self-medication behavior appears to be a commonplace; and when it is ignorant it may prove dangerous. On the other hand, dispensing errors and consequent adverse outcomes, though not too uncommon, are seldom reported. We report here a case of methotrexateinduced acute vesico-bullous eruptions in a patient of psoriasis who indulged in self-medication and was wrongfully dispensed higher doses of methotrexate. CASE DESCRIPTION: A 50-year-old man was diagnosed with psoriasis two years back and advised tablet methotrexate 20 mg once weekly and folic acid supplementation. He experienced symptoms remission after 8 weeks of treatment and preferred to discontinue the medication. As the psoriatic lesions reappeared four weeks ago, he attended a retail pharmacy for refill of the two-year old prescription. He was obliged by the man in the counter who wrongfully dispensed the medicine and the patient consumed methotrexate 10 mg twice daily. On the 20th days, the patient experienced erythematous, vesico-bullous lesions spread all over the body including both limbs and scalp, with oral mucosal involvement without any history of fever, and with mildly deranged liver function, and presented to the dermatology OPD of a tertiary hospital. He was admitted and treated with injection glucocorticoid and leucovorin. He responded well and completely recovered in a week. A 'probable' causality was adjudged for this serious adverse event by both WHO-UMC scale and Naranjo's algorithm. The reaction was moderately severe (Hartwig's scale) and it was definitively preventable (modified Schumock-Thornton scale). CONCLUSION: This case report highlights the hazard of uninformed Self-medication and irresponsible dispensing behavior resulting in serious drug-related injury.

Protective Efficacy of Secondary Prophylaxis Against Visceral Leishmaniasis in Human Immunodeficiency Virus Coinfected Patients Over the Past 10 Years in Eastern India.

Coinfection with visceral leishmaniasis (VL) and human immunodeficiency virus (HIV) leads to frequent treatment failure, relapse, and death. In this retrospective analysis from eastern India (2005-2015), our primary objective was to ascertain the protective efficacy of secondary prophylaxis with monthly amphotericin B (AmB) given in patients with HIV-VL coinfection toward reducing relapse and mortality rates. The secondary objective was to compare clinical features, laboratory findings, and treatment outcomes in HIV-VL patients in contrast to VL monoinfection. Overall, 53 cases of HIV-VL and 460 cases of VL monoinfection were identified after excluding incomplete records. Initial cure rate was 96.23% in HIV-VL (27 received liposomal AmB and 26 AmB deoxycholate). All patients with initial cure (N = 51) were given antiretroviral therapy. Secondary prophylaxis (N = 27) was provided with monthly 1 mg/kg AmB (15 liposomal, 12 deoxycholate). No relapse or death was noted within 6 months in the secondary prophylaxis group (relapse: none versus 18/24 [75%]; mortality: none versus 11/24 [45.8%]; P < 0.001 for both). Secondary prophylaxis remained the sole significant predictor against death in multivariate Cox regression model (hazard ratio = 0.09 [95% confidence interval = 0.03-0.31]; P < 0.001). HIV-VL patients had higher 6-month relapse rate, less relapse-free 12-month survival, and higher mortality (P < 0.001 each) than VL monoinfection. In conclusion, it appears from this study that secondary prophylaxis with monthly AmB might be effective in preventing relapse and mortality in HIV-VL.

Modulation of regulatory T cells by intranasal allergen immunotherapy in an experimental rat model of airway allergy.

Allergic airway diseases such as asthma and allergic rhinitis are increasing in prevalence worldwide. The theory of an altered Th1/Th2 balance in allergic diathesis has recently been termed a "procrustean paradigm" as it failed to explain many preclinical findings. Regulatory T cells (Treg) have now been shown to be critical in T-cell homeostasis and in the maintenance of peripheral tolerance to allergens. Allergen specific immunotherapy (SIT) has been shown to induce regulatory T cells in allergic patients. Among various types of SIT, intranasal immunotherapy had not been studied in detail for the treatment of allergic airway diseases. So, there was a need to study the contribution of regulatory T cells and their mechanistic pathways following intranasal immunotherapy in-vivo. It had been previously shown that intranasal allergen immunotherapy using Alstonia scholaris pollen extract abrogates allergic airway inflammation with decline in IgE and Th2 cytokine levels. The present study for the first time offers a multi-targeted approach towards attenuation of airway allergy by the generation of CD4+CD25+Foxp3+T cells and other subsets of Treg cells like Tr1 cells, Th3 cells, CTLA4+Treg cells, and also modulation of various Treg cell surface molecules like GITR, OX40, CD39 and CD73 by intranasal immunotherapy in the same animal model. This animal experiment will thus help to chart out newer molecular targets for treating allergic asthma or rhinitis.

Allergen immunotherapy modulates sensitivity of Treg cells to apoptosis in a rat model of allergic asthma.

AIM: To study the apoptosis of Foxp3+ Treg cells following Alstonia scholaris pollen sensitization-challenge and following allergen immunotherapy. MATERIALS & METHODS: Wistar rats were sensitized-challenged with Alstonia scholaris pollen and were further given intranasal immunotherapy. For the analysis of the apoptotic proteins on Treg cells by flow cytometry, multiple gating procedures were followed. RESULTS: Allergen sensitization-challenge increases Annexin-V, Fas, FasL, caspases-8, 9, 3 cytochrome-C, APAF-1, Bax, perforin-1 and granzyme-B on Treg cells which is decreased following intranasal immunotherapy. On the other hand, Bcl-2 expression is decreased in allergy and increased by immunotherapy. CONCLUSION: Apoptosis of Treg cells is increased following allergen sensitization-challenge via extrinsic, intrinsic and perforin/granzyme pathways and allergen immunotherapy decreased the sensitivity to apoptosis of Treg cells.